15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia.

Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.

A multimarker QPCR-based platform for the detection of circulating tumour cells in patients with early-stage breast cancer.

BACKGROUND: The detection of circulating tumour cells (CTCs) has been linked with poor prognosis in advanced breast cancer. Relatively few studies have been undertaken to study the clinical relevance of CTCs in early-stage breast cancer. METHODS: In a prospective study, we evaluated CTCs in the peripheral blood of 82 early-stage breast cancer patients. Control groups consisted of 16 advanced breast cancer patients and 45 healthy volunteers. The CTC detection was performed using ErbB2/EpCAM immunomagnetic tumour cell enrichment followed by multimarker quantitative PCR (QPCR). The CTC status and common clinicopathological factors were correlated to relapse-free, breast cancer-related and overall survival. RESULTS: Circulating tumour cells were detected in 16 of 82 (20%) patients with early-stage breast cancer and in 13 out of 16 (81%) with advanced breast cancer. The specificity was 100%. The median follow-up time was 51 months (range: 17-60). The CTC positivity in early-stage breast cancer patients resulted in significantly poorer relapse-free survival (log rank test: P=0.003) and was an independent predictor of relapse-free survival (multivariate hazard ratio=5.13, P=0.006, 95% CI: 1.62-16.31). CONCLUSION: The detection of CTCs in peripheral blood of early-stage breast cancer patients provided prognostic information for relapse-free survival.

Adaptive multiscale complexity analysis of fetal heart rate.

Per partum fetal asphyxia is a major cause of neonatal morbidity and mortality. Fetal heart rate monitoring plays an important role in early detection of acidosis, an indicator for asphyxia. This problem is addressed in this paper by introducing a novel complexity analysis of fetal heart rate data, based on producing a collection of piecewise linear approximations of varying dimensions from which a measure of complexity is extracted. This procedure specifically accounts for the highly non-stationary context of labor by being adaptive and multiscale. Using a reference dataset, made of real per partum fetal heart rate data, collected in situ and carefully constituted by obstetricians, the behavior of the proposed approach is analyzed and illustrated. Its performance is evaluated in terms of the rate of correct acidosis detection versus the rate of false detection, as well as how early the detection is made. Computational cost is also discussed. The results are shown to be extremely promising and further potential uses of the tool are discussed. MATLAB routines implementing the procedure will be made available at the time of publication.

Methodology for multifractal analysis of heart rate variability: from LF/HF ratio to wavelet leaders.

The present contribution aims at proposing a comprehensive and tutorial introduction to the practical use of wavelet Leader based multifractal analysis to study heart rate variability. First, the theoretical background is recalled. Second, practical issues and pitfalls related to the selection of the scaling range or statistical orders, minimal regularity, parabolic approximation of spectrum and parameter estimation, are discussed. Third, multifractal analysis is connected explicitly to other standard characterizations of heart rate variability: (mono)fractal analysis, Hurst exponent, spectral analysis and the HF/LF ratio. This review is illustrated on real per partum fetal ECG data, collected at an academic French public hospital, for both healthy fetuses and fetuses suffering from acidosis.

Vbeta usage and T regulatory cells in children following partial or total thymectomy after open heart surgery in infancy.

During open heart surgery in infants the thymus was usually removed, partly or completely. Our previous studies on 16 such children indicated reduced T-cell output later in life with signs of extrathymic maturation of the T cells, but no reduction in T regulatory cells (CD4+CD25+). The diversity of the T-cell repertoire in these children was examined to test if the extrathymic microenvironment could alter Vbeta usage. The expression of Foxp3 and CD127 in CD4+CD25(high) T cells was measured in order to determine whether the T regulatory cells had the phenotype of natural T regulatory cells. There was a wide distribution of Vbeta usage in both study and control groups. Significant variability was found in Vbeta usage for CD4+ and CD8+ T cells when the distribution of the percentage of T cells expressing each Vbeta family was analysed between individuals within each group (P < 0.001; Kruskal-Wallis). Significant difference was also found in average usage of Vbeta2, Vbeta5.1 and Vbeta14 chains within CD4+ T cells and Vbeta2, Vbeta8 and Vbeta21.3 chains within CD8+ cells between the groups (P < 0.05; Student's t-test). There was no difference between the two groups with regard to the proportion of CD4+CD25(high) T cells and no difference in the average expression of Foxp3 or CD127 within the CD4+CD25(high) population. Our data provide evidence that cardiothoracic surgery in infants and total or partial thymectomy alters Vbeta usage, suggesting more limited selection in such children than in the control group. The frequency of natural T regulatory cells seems to be unimpaired.

Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer.

Sunitinib has been registered for the treatment of advanced renal cell cancer (RCC). As patient inclusion was highly selective in previous studies, experience with sunitinib in general oncological practice remains to be reported. We determined the efficacy and safety of sunitinib in patients with advanced RCC included in an expanded access programme. ECOG performance status >1, histology other than clear cell and presence of brain metastases were no exclusion criteria. Eighty-two patients were treated: 23% reached a partial response, 50% had stable disease, 20% progressed and six patients were not evaluable. Median progression-free survival (PFS) was 9 months and median overall survival (OS) was 15 months. Importantly, 47 patients (57%) needed a dose reduction, 35 (43%) because of treatment-related adverse events, 10 (12%) because of continuous dosing, and two because of both. Stomatitis, fatigue, hand-foot syndrome and a combination of grade 1-2 adverse events were the most frequent reasons for dose reduction. In 40 patients (49%), there was severe toxicity, defined as dose reduction or permanent discontinuation, which was highly correlated with low body surface area, high age and female gender. On the basis of age and gender, a model was developed that could predict the probability of severe toxicity.

Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer.

Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor cyclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m-2 combined with CsA 10 mg kg-1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m-2 week-1. Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter- and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer.

The influence of partial or total thymectomy during open heart surgery in infants on the immune function later in life.

Infants undergoing open heart surgery often have all or part of their thymus removed. The activity of the immune system has not been investigated thoroughly in these children, and only shortly after the operation. Therefore, it was decided to investigate the activity of the immune system in more detail in children several years after their operation. Peripheral blood samples from 19 children who had undergone open heart surgery during their first months of life was collected (study group) and from 19 age- and gender-matched children (control group). The activity of the immune system was evaluated by measuring the number of different cell types in peripheral blood, the phenotype of lymphocytes and the response of T cells following in vitro stimulation by mitogen, tetanus toxoid and measles antigen. The study group had significantly lower counts of total lymphocytes, which was reflected in a lower number of T cells but not B cells. Furthermore, the study group had significantly lower proportion of T cells (CD3(+)) and helper T cells (CD4(+)), but not cytotoxic T cells (CD8(+)). The level of neutrophils in peripheral blood was significantly higher in the study group. This may indicate enhanced innate immunity when the acquired immunity is defective. The results indicate a shift to extrathymic T cell maturation, which is less efficient for CD4(+) helper cells than for CD8(+) cytotoxic cells.

Recovery of astaxanthin from seafood wastewater utilizing fish scales waste.

The paper presents basic data on astaxanthin adsorption from fisheries wastewater to fish scales. This process has been proposed to be applicable in fisheries and shrimp waste management [Helgason, Recovery of compounds using a natural adsorbent, Patent WO 01/77230, 2001]. The innovative feature of the method is the application of a solid waste (fish scales) as a natural adsorbent for a carotenoid pigment (astaxanthin) from the seafood industry wastewater. The model investigations were performed with pure synthetic carotenoids to exclude the role of matrix in which astaxanthin is present in the wastewater. Under the experimental conditions used, the maximum loading capacity of astaxanthin onto the scales is 360 mg kg(-1) dry wt. Studies of the thus formed value added product indicated that drying causes significant loss of astaxanthin activity. Due to the effective filtration characteristics of the studied sorption material, we suggest the scale/astaxanthin sorption process to be suitable for treatment of wastewater from different industries.

Spontaneous closure of atrial septal defects.

Atrial septal defects (ASDs) are found more frequently in the pediatric population than in adults, and improved diagnostic techniques with echocardiography (2DE) and Doppler facilitate diagnosis so that repair is possible at an optimal time. The purpose of our investigation was to study the size of ASDs at diagnosis, how size changes during follow-up, and to explore the relationship between size at diagnosis and need for surgery. We reviewed the medical records of all patients in Iceland with the diagnosis of ASD born between 1984 and 1993. ASD was confirmed by 2DE in all patients and defects smaller than 4 mm were excluded. ASD size was measured by 2DE from subxyphoid long and short axis views. There were 91 patients-29 males and 62 females. Four patients died from causes other than the heart defect and had not been operated upon. Seven patients with ASD primum and sinus venosus defects were excluded from analysis. There were 29 patients with a 4 mm defect, 17 patients with 5 or 6 mm defects, 8 patients with 7 or 8 mm defects, and 26 patients had defects >8 mm. In the 4 mm group, in 26 patients (89%) the ASD closed spontaneously or decreased in size, and 1 patient had been operated upon. In the 5 or 6 mm group, 15 of 19 ASDs (79%) had closed spontaneously, and 2 patients (9.5%) had been operated upon. In the 7 or 8 mm group, 1 of 6 ASDs (16.6%) had closed spontaneously and 3 had been closed surgically. In the >8 mm group, 1 of 24 ASDs had closed spontaneously and 20 (91%) had been closed surgically. We conclude that defects smaller than 6 mm in diameter are very likely to close spontaneously although follow-up is necessary. Defects larger than 8 mm have a high probability requiring operative closure.

[Kawasaki disease in Iceland 1979-1997.].

Kawasaki disease is a multisystem inflammatory disease most commonly affecting young children. The first patient documented with the disease in Iceland was diagnosed in 1979. In this retrospective study we describe our experience with the disease in Iceland over 19 years. From 1979 to 1997 40 children were diagnosed with Kawasaki disease, i.e. an annual incidence of 8.5 per 100,000 children younger than five years of age. Male-female ratio was 2:1. The number of patients each year varied from none to seven. Coronary aneurisms were revealed in four of 30 patients (13%) undergoing 2D echocardiography. One patient died (2.5%) of cardiac complication (heart failure). Twenty-seven of 30 patients diagnosed after 1987 were treated with intravenous immunoglobulins. The incidence of Kawasaki disease in Iceland is comparable to what has been reported in the other Nordic countries.

[Transposition of the great arteries in Iceland over a 26 year period from 1971 to 1996.].

OBJECTIVE: We reviewed our experience regarding D- and L-transposition of the great arteries (D- and L-TGA) in Iceland over a 26 year period, from 1971 to 1996. We looked at incidence, diagnosis, treatment and outcome and any changes in these parameters during the study period were noted. MATERIAL AND METHODS: Data were obtained from hospital records which contained echocardiographic, cardiac catheterization- and autopsy reports. RESULTS: There were 31 children diagnosed as having transposition of the great arteries during the study period, 29 had D-TGA. Follow-up period was from 11 months to 21 years (median 13 years). The incidence was 1:3681 births and male to female ratio 2.4:1. Cardiac catheterization was used as a diagnostic tool in 11 cases, but as of 1984 all diagnoses were made by echocardiography. Of the patients with D-TGA, 21 (72%) had no additional cardiac defects, however when these were present, a ventricular septal defect was most common. Twenty-six patients (84%) underwent a balloon atrial septostomy and it was successful in 24 (92%). Twenty-three of 31 patients (74%) have had cardiac surgery, all fully corrective. Of the 23 surgeries, 21 were done in London, England. Fifteen children had atrial switch repair, a Mustard operation was done twice and Senning in 13 patients. In five cases an arterial switch operation was performed and three patients had other surgeries. Half of the patients had a difficult post operative course, however there was only one death within the first month following surgery. Of the 31 children born with TGA from 1971 to 1996, eight (26%) have died and two are lost to follow-up. All the patients that died were born during the first half of the study period. Of these eight children, four died within the first four days of life. Corrective cardiac surgery had been done on two patients before death. There are 21 patients alive which updated information is available on. All are in good condition leading full active lives. Five patients are needing prescription medications, thereof two antiarrhythmics. Of the most recent echocardiograms, 16 are without hemo-dynamically significant sequela. In five cases however, echocardiography shows significant abnormalities, probably warranting intervention within the next few years. CONCLUSIONS: The diagnosis, treatment and outcome of patients with transposition of the great arteries has improved dramatically over the years. Close follow-up of these patients with regards to sequela of cardiac surgery is mandatory, especially since the majority of this patient population has had atrial switch repair.

Echocardiographic evaluation of systolic and diastolic function in postoperative coarctation patients.

Postoperative coarctation (CoA) patients are often found to have signs of persistent myocardial dysfunction. M-mode echocardiography was performed to study left ventricular (LV) size, mass, and systolic function and Doppler ultrasonography to study LV filling and flow velocity in the LV outflow tract and aorta in 28 "healthy" postoperative CoA patients (5-21 years) and 28 age- and sex-matched controls. The early (E) and late (A) diastolic transmitral velocities were significantly higher in the patient group than in the controls (p < 0.05). Other diastolic parameters (isovolumic relaxation time, E/A ratio, and deceleration time of the early diastolic velocity) were similar in the two groups (p = NS). The left atrial diameter, LV wall average, end-diastolic diameter of the LV and LV mass were higher in the patients than controls (p < 0.05). The patients also had a higher stroke volume, cardiac output, and cardiac index than the controls (p < 0.01). The fractional shortening was similar in the two groups (p = NS). Blood flow velocities in both the LV outflow tract and aorta were higher in the patients than the controls (p < 0.0002). We found LV hypertrophy with signs of a hyperdynamic circulation (increased cardiac index and stroke volume) in our patients. An increase in A is associated with LV hypertrophy and seems to be a sensitive marker of diastolic abnormality. The rise in E is paradoxical but has been seen in other studies. The increased blood flow velocity in the LV outflow tract suggests obstruction to LV outflow and increased flow in the descending aorta is due to residual coarctation.

[A left main coronary artery arising from the pulmonary artery. Case report.].

Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenitial heart disease. Most patients are diagnosed shortly after birth but occasionally the anomaly is diagnosed in teenagers or adults. Prognos is dismal without operation. We describe the first case diagnosed and treated in Iceland. The patient, an asymptomatic 14 year old boy, underwent both the socalled Takeuchi's tunnel plastic and a coronary bypass operation.

[Congenital heart defects in Icelandic twins.].

OBJECTIVE: Several investigations have been published on the incidence of congenital heart defects (CHD), showing the incidence to be 0.8-1.1%. Few studies have dealt with the incidence of CHD in twins, but they indicate higher incidence of CHD among twins compared to singletons. The purpose of this study was to investigate the incidence of CHD and the different types of defects among twins born in Iceland over a 10 year period and compare the data to the incidence of CHD in the Icelandic population. MATERIAL AND METHODS: Information was obtained on all twins born alive in Iceland from 1986-1995 at the Icelandic Statistical Bureau. That list was compared to a list of all children born in Iceland over the same period and diagnosed with CHD, thus finding all twins with diagnosed CHD. The incidence of CHD for the period of 1986-1990 and 1991-1995 was studied separately. Causes of death, whether the patients needed treatment or not, and the results of treatment were studied. Chi-squared test for statistical analysis was used when appropriate. RESULTS: Incidence: Of 1089 liveborn twins 35 had CHD or 3.21% compared to an incidence rate of 1.0% among singletons, which is a statistically significant difference (p<0.001). The incidence was 2.13% in the years 1986-1990 and 3.78% in the years 1991-1995 (p<0.005). Types of defects: Of 35 twins with CHD 20 had minor defects (no treatment needed) whereas 15 had major defects. Ventricular septal defects were the most common defects encountered, or 40%, atrial septal defects were 20%, patent ductus arteriosus 9%, complex defects 9% and tetralogy of Fallot 6%. Other defects were less common. Sex ratio: The male/female ratio was 0.591, whereas the ratio in the control population was 1.1. However, this did not reach statistical difference (p>0.05). Twin types: Of the twins with CHD 34% were male-female pairs, 26% were male-male pairs and 40% were female-female pairs. Age at diagnosis: Thirteen patients were diagnosed in the first week of life and 20 from one week to five months of age. After six months of age only two patients have been diag notnosed with CHD. TREATMENT: Twelve patients have been operated for CHD, one patient was treated in an interventional cardiac catheterization and 10 patients received medical treatment. Mortality: Six twins died as a consequence of their heart defect (17%). The mortality rate was significantly higher among twins with major CHD compared to the control population (p<0.005). CONCLUSION: Congenital heart defects are more common among twins compared to the control group. They were also more common in the latter half of the investigation period. The mortality rate is also higher among the twins. In 1991 in titero fertilization was started in Iceland resulting in increased number of twins and at the same time increase in incidence of CHD is seen. Further studies are required to clarify this.

Exercise-induced hypertension after corrective surgery for coarctation of the aorta.

The purpose of this investigation was to study exercise-induced hypertension after surgical repair of coarctation of the aorta (CoA). Groups of 27 patients with CoA and 27 healthy control subjects, 6-21 years old, were exercised to exhaustion using the Bruce protocol. Fourteen patients had undergone surgery during the first year of life (group A), and 13 patients had been operated on later (group B). The pulse rate and systolic blood pressures (BP) in the arm and leg were measured before, during, and after exercise to evaluate changes in the BP and the arm/leg BP gradient with exercise. The systolic BP was significantly higher in the patients than in the controls at all stages of the exercise test (p < 0.01), as was the arm/leg BP gradient both before and after exercise (p < 0.01); the latter increased significantly with exercise in the patient group (p < 0.05). We found hypertension to be a more common and severe problem in group B patients, who had higher blood pressures than their controls at rest and during exercise (p < 0.05). Exercise-induced hypertension was also more common in group B (23%) than in group A (7%). We conclude that exercise-induced hypertension and recoarctation are problems in postoperative CoA patients. Moreover, exercise-induced hypertension is more common in patients with CoA operated on after the first year of life.

[Cardiac surgery because of congenital heart disease on Icelandic children born 1969-1993.].

The incidence of congenital heart disease (CHD) has been shown to be 0.8-1.0% and of these 0.5% will require specific treatment. An investigation on Icelandic children born 1985-1989 showed a slightly higher incidence or 1.1%. Iceland is well suited for population studies because investigation, treatment or treatment decision are made centrally, the population is stable and the country geographically well defined. The purpose of our study was to investigate the number of Icelandic children who required cardiac surgery because of CHD, the distribution between specific defects, the number of operations, age at first operation, mortality and causes of death. The study deals with children born in Iceland from 1969 to 1993 that had been operated upon for CHD during the period January 1st 1969 to May 1st 1994. Data were collected from the Departments of Pediatrics, Surgery and Medicine of Landspitalinn, National University Hospital. During this 25 year period 299 children had 354 operations because of CHD or 2.75 per 1000 livebirths. The mean age at operation has fallen from 4.7 years in 1969-1973 to 0.8 years in 1989-1993. Operations done in England were 261 and 79 in Iceland. The most commonly encountered defect was ventricular septal defect (VSD). During the study period the frequency of operations for the individual defects was stable except for atrial septal defect (ASD) which increased after 1984. Of the 299 children 31 are dead (10.4%). Of 1000 live born children 2.75 will require cardiac surgery because of CHD. The reason for reduced age at operation and increasing operation frequency for ASD are probably because of better diagnostic technique and improved knowledge about the disease process.

[Atrial septal defects in Iceland.].

Atrial septal defects (ASD) are common congenital heart defects (CHD), 15-22% of all CHD. The diagnosis of ASD is often delayed due to nonspecific symptoms and faint heart murmur and needs confirmation by echocardiography (2 DE). The aim of our study is to study the incidence of ASD, associated defects, and operative results in patients in our population of 260,000. We reviewed the medical records of all patients diagnosed in Iceland with the diagnosis of ASD born in 1984-93. There were 43,809 births during that period. The ASD was confirmed by 2DE in all patients and smaller defects than 4 mm were excluded. There were 87 patients, 61 female and 26 male; male/female = 1:2,4. The number of patients increased during the period; 1984-85 four patients, 1986-87 12 patients, 1988-89 19 patients, 1990-91 22 patients and 1992-93 30 patients. The incidence in 1984-85 was 0.5/1000 and in 1992-93 2.6/1000. The ASD types were: ASD secundum 79 patients, ASD primum three patients and sinus venosus ASD five patients. The symptoms that lead to cardiac evaluation were most often heart murmur with (22%) or without (62%) other symptoms. However 16% of the patients did not have murmur as a referral diagnosis. There were 26 (30%) patients with other congenital anomalies (Down's syndrome eight patients, other chromosomal defects three patients, 15 patients with other congenital defects) and 29 (33%) patients also had a minor cardiac defect. Four patients died, all from other causes than the cardiac defect, none of whom had been operated. There were 34 (39%) patients who will or have already been operated, in 29 (33%) patients the ASD has closed spontaneously and in 12 (14%) patients the ASD size had decreased so there was no need for an operation. There were no deaths from operation and one patient had a minor complication. In conclusion ASD is a more common problem in childhood than previously reported and often these patients have significant associated problems. Vague symptoms and often inconspicuous heart murmur often delay diagnosis. The surgery for ASD is safe and longterm prognosis favorable.